The international phase III DESTINY-Gastric04 clinical trial found that second-line treatment with fam-trastuzumab deruxtecan-nxki can help people with advanced HER2-positive gastric cancers that have grown during first-line treatment live about 3 months longer. These findings further support the use of trastuzumab deruxtecan in the second-line setting for these patients. The research will be presented at the 2025 ASCO Annual Meeting (Abstract LBA4002).
Study Design
“If disease progression occurs in the first-line metastatic setting of HER2-positive gastric cancer, there historically have been no HER2-directed medicines that have demonstrated a survival benefit in a phase III clinical trial in the second-line setting. The results of DESTINY-Gastric04 show that second-line treatment with HER2-directed trastuzumab deruxtecan can extend survival compared to a chemotherapy-based regimen,” said lead study author Kohei Shitara, MD, Director of the Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
People with metastatic gastric cancer often have a poor prognosis, with a 5-year survival rate ranging from 5% to 10%. About 5% to 17% of these cancers are HER2-positive. For people with metastatic HER2-positive gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma that has progressed during first-line treatment, a standard second-line treatment option is paclitaxel with ramucirumab. Historically, there have not been any treatments that directly target the HER2 protein for people with metastatic HER2-positive gastric cancer in the second-line setting.
Trastuzumab deruxtecan is a targeted therapy drug that directly targets the HER2 protein on cancer cells. Based on results from previous phase II clinical trials, trastuzumab deruxtecan has been approved in more than 65 countries for people with advanced HER2-positive gastric cancer or GEJ adenocarcinoma who have previously received treatment with a trastuzumab-based regimen. The DESTINY-Gastric04 clinical trial is the first phase III clinical trial to directly compare trastuzumab deruxtecan against paclitaxel with ramucirumab in the second-line setting for these patients.
Key Findings
DESTINY-Gastric04 included 494 patients with metastatic or unresectable HER2-positive gastric cancer or GEJ adenocarcinoma that had progressed during or after treatment with a trastuzumab-based regimen. The median age of the patients was about 64 years old, and most of the patients were from Western Europe or Asia. The patients were randomly assigned to receive either trastuzumab deruxtecan (n = 246) or paclitaxel with ramucirumab (n = 248). About 60% of the patients in each treatment group had gastric cancer, and about 40% in each group had GEJ adenocarcinoma.
After a median follow-up of 16.8 months for the trastuzumab deruxtecan group and 14.4 months for the standard treatment group, researchers found that trastuzumab deruxtecan helped patients live 3.3 months longer. The median overall survival was 14.7 months for patients who received trastuzumab deruxtecan vs 11.4 months for patients who received paclitaxel with ramucirumab. Trastuzumab deruxtecan reduced the risk of death by 30% for patients.
The median progression-free survival for the trastuzumab deruxtecan group was 6.7 months vs 5.6 months in the standard-treatment group. For the patients in the trastuzumab deruxtecan group, their risk of disease progression was reduced by 26%.
The objective response rate was 44.3% in the trastuzumab deruxtecan group vs 29.1% in the standard treatment group. The disease control rate was 91.9% in the trastuzumab deruxtecan group vs 75.9% for the standard treatment group.
Significance and Next Steps
“Trastuzumab deruxtecan is approved for patients with metastatic HER2-positive gastric cancer or GEJ adenocarcinoma who received a prior trastuzumab-based regimen based on previous phase II studies. The improvement in overall survival with trastuzumab deruxteacan compared to ramucirumab with paclitaxel seen in this study validates the role of trastuzumab deruxtecan in the second-line setting,” said Pamela Kunz MD, PhD, Director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center and an ASCO expert in gastrointestinal cancers.
Researchers will continue to study the safety and efficacy of trastuzumab deruxtecan for people with HER2-positive gastric cancer in the first-line setting in three separate clinical trials: DESTINY-Gastric05, DESTINY-Gastric03, and ARTEMIDE-Gastric01.
Disclosure: This study was sponsored by Daiichi Sankyo, Inc. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201). For full disclosures of the study authors, visit coi.asco.org.
